Physiologically Based Pharmacokinetic Model for Drugs Encapsulated into Liposomes

摘要 尽管脂质体在药物输送方面有很大的希望，脂质体药物的数量也得到了批准， 这类药物及其后续版本的开发仍然面临挑战。目前，这一领域正面临着 “论文多，药品少”的两难境地。造成这一局面的因素有很多。一个重要因素 开发的复杂性是否与脂质体的物理化学性质有关，其中一分钟 差异可能会导致体内表现和治疗效果的根本性变化。另一个关键因素是 缺乏有效的战略来利用药物开发方面不断增加的研究和知识。 开发的复杂性也给监管决策带来了挑战。在这里，我们提出一种 基于生理的药代动力学(PBPK)建模策略来应对这些挑战。这一战略 为脂质体药物开发专门的PBPK平台，有望实现有效的翻译 物理化学性质与体内性能之间的关系，允许开发者和 监管机构，最终加快药物开发。这一战略的一个关键特点是将“模型”和“模型” 以动态和顺序的方式进行“实验”。一方面，PBPK模型提供了先前的模拟 指导实验设计；此外，实验生成新的知识来约束PBPK模型 这将有利于进一步的实验。阿霉素脂质体(Doxil®)被选为模型药物。仿制药 Model将逐步成长为专业的PBPK平台，并包含更具体的 通过严格的文献研究或额外的实验获得关于脂质体阿霉素的信息。五 具体目标是：目标1：建立基于文库的脂质体药物仿制PBPK模型，用于培训文献- 派生的属性-性能关系。我们的目标是充分利用 文献，寻找脂质体的广泛性质-性能关系，然后训练这些关系 在基于图书馆的通用PBPK模型中探索潜在的关键质量属性(CQA)。目标2： 聚乙二醇化阿霉素系列脂质体的制备、表征及体外研究。这些 将通过修改目标1中计划的CQA来准备配方。本节将产生 更具体的知识，以进一步限制和完善通用的PBPK模型。目标3：评估PK和 所需制剂的生物分布。该制剂的性能将与体内性能匹配，以 更新PBPK模型。目的4：定量脂质体在实体瘤中的异质性分布并探索 决定因素。在目标4之后，pbpk模型将完成一个级联，该级联来自于“公式属性→系统 Returant→异质肿瘤处置→功效“。目标5：模型验证和翻译。模型 向人类的转换将通过基于机构的蒙特卡罗模拟来执行。一个“虚拟的” 将进行生物等效性研究。

ABSTRACT Despite the great promise held for liposomes in drug delivery and the number of liposomal drugs approved, challenges remain in development of such drugs and their follow-on versions. Currently, this field is confronting a dilemma of “so many papers and so few drugs”. A number of factors contribute to this. One significant factor is the development complexity pertaining to the physicochemical properties of liposomes, where a minute difference may result in a radical change in in vivo performance and treatment efficacy. Another critical factor is a lack of effective strategies to leverage the mounting research and knowledge in drug development. Development complexity also poses challenges to regulatory decision-making. Here we propose a physiologically-based pharmacokinetic (PBPK) modeling strategy to address these challenges. This strategy develops a specialized PBPK platform for liposomal drugs that is expected to enable effective translations from physicochemical properties to in vivo performance, allowing early interactions between developers and regulators, ultimately expediting drug development. A key feature of this strategy is to integrate “model” and “experiment” in a dynamic and sequential manner. On one side, PBPK models provide a prior simulation to guide experimental design; additionally, the experiment generates new knowledge to constrain PBPK models that will benefit further experimentation. Liposomal doxorubicin (Doxil®) is chosen as a model drug. A generic model will step-wisely grow into a specialized PBPK platform along with the inclusion of more specific information about liposomal doxorubicin either by rigorous literature research or additional experiments. Five Specific Aims are: Aim 1: Build a library-based generic PBPK model for liposomal drugs to train literature- derived property-performance relationships. The objective is to leverage the vast amount of knowledge in the literature, seeking broad property-performance relationships for liposomes and then training these relationships in a library-based generic PBPK model to explore potential Critical Quality Attributes (CQAs). Aim 2: Preparation, characterization, and in vitro studies of a series of PEGylated liposomal doxorubicin. These formulations will be prepared with modifications of the CQAs that are projected in Aim 1. This section will yield more specific knowledge to further confine and improve the generic PBPK model. Aim 3: Assess the PK and biodistribution of the desired formulations. The formulation properties will match with in vivo performance to update PBPK model. Aim 4: Quantify the heterogeneous distribution of liposomes in solid tumors and explore the determinants. After Aim 4, the PBPK model will complete a cascade from “formulation properties → system retention → heterogeneous tumor disposition → efficacy”. Aim 5: Model validation and translation. The model translation to human will be performed by mechanism-based Monte Carlo Simulation. A “virtual” bioequivalence study will be conducted.